Certain aryl substituted pyrrolopyrazines; a new class of GABA brain receptor ligands

ABSTRACT

This invention encompasses compounds of the formula: ##STR1## and pharmaceutically acceptable non-toxic salts thereof wherein: ##STR2##  represents: ##STR3##  where n is 0, 1, or 2; R 1  and R 2  are hydrogen or straight or branched chain alkyl groups; 
     Y represents various organic and inorganic substituents; 
     W represents an aromatic group substituted with various organic and inorganic substituents; 
     A is CH or N; 
     B is a substituted or unsubstituted carbon or N; and 
     E is hydrogen or straight or branched alkyl groups 
     These compounds are highly selective agonists, antagonists or inverse agonists for GABAa brain receptors or prodrugs thereof and are useful in the diagnosis and treatment of anxiety, sleep, and seizure disorders, overdose with benzodiazepine type drugs, and enhancement of alertness.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to certain aryl substituted pyrrolopyrazineswhich selectively bind to GABAa receptors. This invention also relatesto pharmaceutical compositions comprising such compounds. It furtherrelates to the use of such compounds in treating anxiety, sleep andseizure disorders, and overdoses of benzodiazepine-type drugs, andenhancing alertness. The interaction of pyrrolopyrazines of theinvention with a GABA binding site, the benzodiazepines (BDZ) receptor,is described. This interaction results in the pharmacological activitiesof these compounds.

2. Description of the Related Art

γ-Aminobutyric acid (GABA) is regarded as one of the major inhibitoryamino acid transmitters in the mammalian brain. Over 30 years haveelapsed since its presence in the brain was demonstrated (Roberts &Frankel, J. Biol. Chem. 187: 55-63, 1950; Udenfriend, J. Biol. Chem.187: 65-69, 1950). Since that time, an enormous effort has been devotedto implicating GABA in the etiology of seizure disorders, sleep, anxietyand cognition (Tallman and Gallager, Ann. Rev. Neuroscience 8: 21-44,1985). Widely, although unequally, distributed through the mammalianbrain, GABA is said to be a transmitter at approximately 30% of thesynapses in the brain. In most regions of the brain, GABA is associatedwith local inhibitory neurons and only in two regions is GABA associatedwith longer projections. GABA mediates many of its actions through acomplex of proteins localized both on cell bodies and nerve endings;these are called GABAa receptors. Postsynaptic responses to GABA aremediated through alterations in chloride conductance that generally,although not invariably, lead to hyperpolarization of the cell. Recentinvestigations have indicated that the complex of proteins associatedwith postsynaptic GABA responses is a major site of action for a numberof structurally unrelated compounds capable of modifying postsynapticresponses to GABA. Depending on the mode of interaction, these compoundsare capable of producing a spectrum of activities (either sedative,anxiolytic, and anticonvulsant, or wakefulness, seizures, and anxiety).

1,4-Benzodiazepines continue to be among the most widely used drugs inthe world. Principal among the benzodiazepines marketed arechlordiazepoxide, diazepam, flurazepam, and triazolam. These compoundsare widely used as anxiolytics, sedative-hypnotics, muscle relaxants,and anticonvulsants. A number of these compounds are extremely potentdrugs; such potency indicates a site of action with a high affinity andspecificity for individual receptors. Early electrophysiological studiesindicated that a major action of benzodiazepines was enhancement ofGABAergic inhibition. The benzodiazepines were capable of enhancingpresynaptic inhibition of a monosynaptic ventral root reflex, aGABA-mediated event (Schmidt et al., 1967, Arch. Exp. Path. Pharmakol.258: 69-82). All subsequent electrophysiological studies (reviewed inTallman et al. 1980, Science 207:274-81, Haefley et al., 1981, Handb.Exptl. Pharmacol. 33:95-102) have generally confirmed this finding, andby the mid-1970s, there was a general consensus amongelectrophysiologists that the benzodiazepines could enhance the actionsof GABA.

With the discovery of the "receptor" for the benzodiazepines and thesubsequent definition of the nature of the interaction between GABA andthe benzodiazepines, it appears that the behaviorally importantinteractions of the benzodiazepines with different neurotransmittersystems are due in a large part to the enhanced ability of GABA itselfto modify these systems. Each modified system, in turn, may beassociated with the expression of a behavior.

Studies on the mechanistic nature of these interactions depended on thedemonstration of a high-affinity benzodiazepine binding site (receptor).Such a receptor is present in the CNS of all vertebratesphylogenetically newer than the boney fishes (Squires & Braestrup 1977,Nature 166: 732-34, Mohler & Okada, 1977, Science 198: 854-51, Mohler &Okada, 1977, Br. J. Psychiatry 133: 261-68). By using tritiateddiazepam, and a variety of other compounds, it has been demonstratedthat these benzodiazepine binding sites fulfill many of the criteria ofpharmacological receptors; binding to these sites in vitro is rapid,reversible, stereospecific, and saturable. More importantly, highlysignificant correlations have been shown between the ability ofbenzodiazepines to displace diazepam from its binding site and activityin a number of animal behavioral tests predictive of benzodiazepinepotency (Braestrup & Squires 1978, Br. J. Psychiatry 133: 249-60, Mohler& Okada, 1977, Science 198: 854-51, Mohler & Okada, 1977, Br. J.Psychiatry 133: 261-68). The average therapeutic doses of these drugs inman also correlate with receptor potency (Tallman et al. 1980, Science207: 274-281).

In 1978, it became clear that GABA and related analogs could interact atthe low affinity (1 μM) GABA binding site to enhance the binding ofbenzodiazepines to the clonazepan-sensitive site (Tallman et al. 1978,Nature, 274: 383-85). This enhancement was caused by an increase in theaffinity of the benzodiazepine binding site due to occupancy of the GABAsite. The data were interpreted to mean that both GABA andbenzodiazepine sites were allosterically linked in the membrane as partof a complex of proteins. For a number of GABA analogs, the ability toenhance diazepam binding by 50% of maximum and the ability to inhibitthe binding of GABA to brain membranes by 50% could be directlycorrelated. Enhancement of benzodiazepine binding by GABA agonists isblocked by the GABA receptor antagonist (+) bicuculline; thestereoisomer (-) bicuculline is much less active (Tallman et al., 1978,Nature, 274: 383-85).

Soon after the discovery of high affinity binding sites for thebenzodiazepines, it was discovered that a triazolopyridazine couldinteract with benzodiazepine receptors in a number of regions of thebrain in a manner consistent with receptor heterogeneity or negativecooperativity. In these studies, Hill coefficients significantly lessthan one were observed in a number of brain regions, including cortex,hippocampus, and striatum. In cerebellum, triazolopyridazine interactedwith benzodiazepine sites with a Hill coefficient of 1 (Squires et al.,1979, Pharma. Biochem. Behav. 10: 825-30, Klepner et al. 1979,Pharmacol. Biochem. Behav. 11: 457-62). Thus, multiple benzodiazepinereceptors were predicted in the cortex, hippocampus, striatum, but notin the cerebellum.

Based on these studies, extensive receptor autoradiographic localizationstudies were carried out at a light microscopic level. Although receptorheterogeneity has been demonstrated (Young & Kuhar 1980, J. Pharmacol.Exp. Ther. 212: 337-46, Young et al., 1981 J. Pharmacol Exp. ther 216:425-430, Niehoff et al. 1982, J. Pharmacol. Exp. Ther. 221: 670-75), nosimple correlation between localization of receptor subtypes and thebehaviors associated with the region has emerged from the early studies.In addition, in the cerebellum, where one receptor was predicted frombinding studies, autoradiography revealed heterogeneity of receptors(Niehoff et al., 1982, J. Pharmacol. Exp. Ther. 221: 670-75).

A physical basis for the differences in drug specificity for the twoapparent subtypes of benzodiazepine sites has been demonstrated bySieghart & Karobath, 1980, Nature 286: 285-87. Using gel electrophoresisin the presence of sodium dodecyl sulfate, the presence of severalmolecular weight receptors for the benzodiazepines has been reported.The receptors were identified by the covalent incorporation ofradioactive flunitrazepam, a benzodiazepine which can covalently labelall receptor types. The major labeled bands have molecular weights of50,000 to 53,000, 55,000, and 57,000 and the triazolopyridazines inhibitlabeling of the slightly higher molecular weight forms (53,000, 55,000,57,000) (Seighart et al. 1983, Eur. J. Pharmacol. 88: 291-99).

At that time, the possibility was raised that the multiple forms of thereceptor represent "isoreceptors" or multiple allelic forms of thereceptor (Tallman & Gallager 1985, Ann. Rev. Neurosci. 8, 21-44).Although common for enzymes, genetically distinct forms of receptorshave not generally been described. As we begin to study receptors usingspecific radioactive probes and electrophoretic techniques, it is almostcertain that isoreceptors will emerge as important in investigations ofthe etiology of psychiatric disorders in people.

The GABAa receptor subunits have been cloned from bovine and human cDNAlibraries (Schoenfield et al., 1988; Duman et al., 1989). A number ofdistinct cDNAs were identified as subunits of the GABAa receptor complexby cloning and expression. These are categorized into α, β, γ, δ, ε, andprovide a molecular basis for the GABAa receptor heterogeneity anddistinctive regional pharmacology (Shivvers et al., 1980; Levitan etal., 1989). The γ subunit appears to enable drugs like benzodiazepinesto modify the GABA responses (Pritchett et al., 1989). The presence oflow Hill coefficients in the binding of ligands to the GABAa receptorindicates unique profiles of subtype specific pharmacological action.

Drugs that interact at the GABAa receptor can possess a spectrum ofpharmacological activities depending on their abilities to modify theactions of GABA. For example, the beta-carbolines were first isolatedbased upon their ability to inhibit competitively the binding ofdiazepam to its binding site (Nielsen et al., 1979, Life Sci. 25:679-86). The receptor binding assay is not totally predictive about thebiological activity of such compounds; agonists, partial agonists,inverse agonists, and antagonists can inhibit binding. When thebeta-carboline structure was determined, it was possible to synthesize anumber of analogs and test these compounds behaviorally. It wasimmediately realized that the beta-carbolines could antagonize theactions of diazepam behaviorally (Tenen & Hirsch, 1980, Nature 288:609-10). In addition to this antagonism, beta-carbolines possessintrinsic activity of their own opposite to that of the benzodiazepines;they become known as inverse agonists.

In addition, a number of other specific antagonists of thebenzodiazepine receptor were developed based on their ability to inhibitthe binding of benzodiazepines. The best studied of these compounds isan imidazodiazepine, (Hunkeler et al., 1981, Nature 290: 514-516). Thiscompound is a high affinity competitive inhibitor of benzodiazepine andbeta-carboline binding and is capable of blocking the pharmacologicalactions of both these classes of compounds. By itself, it possesseslittle intrinsic pharmacological activity in animals and humans(Hunkeler et al., 1981, Nature 290: 514-16; Darragh et al., 1983, Eur.J. Clin. Pharmacol. 14: 569-70). When a radiolabeled form of thiscompound was studied (Mohler & Richards, 1981, Nature 294: 763-65), itwas demonstrated that this compound would interact with the same numberof sites as the benzodiazepines and beta-carbolines, and that theinteractions of these compounds were purely competitive. This compoundis the ligand of choice for binding to GABAa receptors because it doesnot possess receptor subtype specificity and measures each state of thereceptor.

The study of the interactions of a wide variety of compounds similar tothe above has led to the categorizing of these compounds. Presently,those compounds possessing activity similar to the benzodiazepines arecalled agonists. Compounds possessing activity opposite tobenzodiazepines are called inverse agonists, and the compounds blockingboth types of activity have been termed antagonists. This categorizationhas been developed to emphasize the fact that a wide variety ofcompounds can produce a spectrum of pharmacological effects, to indicatethat compounds can interact at the same receptor to produce oppositeeffects, and to indicate that beta-carbolines and antagonists withintrinsic anxiogenic effects are not synonymous. A biochemical test forthe pharmacological and behavioral properties of compounds that interactwith the benzodiazepine receptor continues to emphasize the interactionwith the GABAergic system. In contrast to the benzodiazepines, whichshow an increase in their affinity due to GABA (Tallman et al., 1978,Nature 274: 383-85, Tallman et al., 1980, Science 207: 274-81),compounds with antagonist properties show little GABA shift (i.e.,change in receptor affinity due to GABA) (Mohler & Richards 1981, Nature294: 763-65 ), and the inverse agonists actually show a decrease inaffinity due to GABA (Braestrup & Nielson 1981, Nature 294: 472-474).Thus, the GABA shift predicts generally the expected behavioralproperties of the compounds.

Various compounds have been prepared as benzodiazepine agonists andantagonists. For Example, U.S. Pat. Nos. 3,455,943, 4,435,403,4,596,808, 4,623,649, and 4,719,210, German Patent No. DE 3,246,932, andLiebigs Ann. Chem. 1986, 1749 teach assorted benzodiazepine agonists andantagonists and related anti-depressant and central nervous systemactive compounds. U.S. Pat. No. 3,455,943 discloses compounds of theformula: ##STR4## wherein R₁ is a member of the group consisting ofhydrogen and lower alkoxy; R₂ is a member of the group consisting ofhydrogen and lower alkoxy; R₃ is a member of the group consisting ofhydrogen and lower alkyl; and X is a divalent radical selected from thegroup consisting of ##STR5## and the non-toxic acid addition saltsthereof.

U.S. Pat. No. 4,435,403 teaches compounds of the formula: ##STR6##wherein R^(C) is hydrogen, lower alkyl, alkoxyalkyl of up to 6 C-atoms,cycloalkyl of 3-6 C-atoms, aralkyl of up to 8 C-atoms, or (CH₂)_(n) OR²⁰

wherein R²⁰ is alkyl of up to 6 C-atoms, cycloalkyl of 3-6 C-atoms oraralkyl of up to 8 C-atoms and n is an integer of 1 to 3;

Y is oxygen, two hydrogen atoms or NOR¹,

wherein R¹ is hydrogen, lower alkyl, aryl or aralkyl of up to 6 C-atoms,COR², wherein R² is lower alkyl of up to 6 C-atoms,

or Y is CHCOOR³, wherein R³ is hydrogen or lower alkyl

or Y is NNR⁴ R⁵,

wherein R⁴ and R⁵ can be the same or different and each is hydrogen,lower alkyl, C₆₋₁₀ -aryl, C₇₋₁₀ -aralkyl or CONR⁶ R⁷,

wherein R⁶ and R⁷ can be the same or different and each is hydrogen orlower alkyl or R⁴ and R⁵ together with the connecting N-atom, form a 5-or 6-membered heterocyclic ring which optionally may also contain anO-atom or up to 3 N-atoms and which optionally may be substituted by alower alkyl group;

Z is hydrogen, or alkoxy or aralkoxy each of up to 10 C-atoms and eachoptionally substituted by hydroxy, or Z is alkyl of up to 6 C-atoms,C₆₋₁₀ -aryl or C₇₋₁₀ -aralkyl each of which may optionally besubstituted by a COOR⁸ or a CONR⁹ R¹⁰ group,

wherein R⁸ is alkyl of up to 6 C-atoms, and R⁹ and R¹⁰ can be the sameor different and each is hydrogen or alkyl of up to 6 C-atoms; or Z isNR⁹ R¹⁰, wherein R⁹ and R¹⁰ are as defined above; or Z is NR¹¹ CHR¹²R¹³,

wherein R¹¹ and R¹² each is hydrogen or together form a N═C double bond,

wherein R¹³ is C₁₋₁₀ -alkyl or NR¹⁴ R¹⁵,

wherein R¹⁴ and R¹⁵ are the same or different and each is hydrogen, OHor alkyl or alkoxy each of up to 6 C-atoms,

or wherein R¹² and R¹³ together are oxygen, in which case, R¹¹ ishydrogen;

or Z is COOR² wherein R² is as defined above;

or Y and Z, together with the connecting C-atom, may form a 5- or6-membered heterocyclic ring which contains an O-atom, adjoining O- andN-atoms or up to a 4N atoms and which optionally may be substituted by alower alkyl group, hydroxy or oxo.

U.S. Pat. No. 4,596,808 discloses compounds of the formula: ##STR7##wherein R^(A) is H, F, CL, Br, I, NO₂, CN, CH₃, CF₃, SCH₃, NR¹⁶ R¹⁷ orNHCOR¹⁶,

wherein R¹⁶ of R¹⁷ are the same or different and each is hydrogen oralkyl, alkenyl or alkynyl each of up to 6 C-atoms, aralkyl or cycloalkyleach of up to 10 C-atoms,

or wherein R¹⁶ and R¹⁷ together form a saturated or unsaturated 3-7membered heterocyclic ring.

U.S. Pat. No. 4,623,649 teaches compounds of the formula: ##STR8##wherein R³ is an oxadiazolyl residue of the formula ##STR9## wherein R⁵stands for lower alkyl of up to 3 carbon atoms or an ester --CO₂ R₆

with R⁶ being hydrogen or lower alkyl of up to 3 carbon atoms,

R⁴ is hydrogen, lower alkyl of up to 3 carbon atoms, or CH₂ OR⁹ wherein

R⁹ is lower alkyl of up to 3 carbon atoms,

R^(A) is phenyl or a hydrocarbon residue containing 2-10 carbon atomswhich can be cyclic or acyclic, saturated or unsaturated, branched orunbranched, and which can optionally be substituted by oxo, formyl OH,O-alkyl of up to 3 carbon atoms or phenyl, and wherein in a cyclichydrocarbon residue, a CH₂ -group can be replaced by oxygen.

U.S. Pat. No. 4,719,210 discloses compounds of the formula: ##STR10##wherein R¹ is hydrogen or a protecting group,

R² is --CH═CR4₂ or --C═CR⁴,

R⁴ is hydrogen or halogen,

R³ is hydrogen, lower alkyl or lower alkoxyalkyl,

R^(A) is, inter alia, hydrogen, OR⁷, lower alkyl, which optionally issubstituted with aryl, lower alkoxy or NR5R6,

R⁵ and R⁶ can be the same or different and in each case is hydrogen,lower alkyl or together with the nitrogen atom a 5-6 member ring, whichcan contain another heteroatom.

R⁷ is lower alkyl, optionally substituted aryl or aralkyl, and

each compound can contain one or more R^(A) radicals which are nothydrogen.

These compounds differ from the compounds of the present invention.These U.S. Patents teach carbocyclic compounds having pyridine orpiperidine rings but lacking the pyrimidine ring present in thecompounds of the present invention. German Patent No. DE 3,246,932discloses compounds of the formula: ##STR11## wherein

R=halo, NO₂, CO₂ H, modified CO₂ H, R² O, R² S(O)_(n) ; n=0-2; and R¹=H, alkyl, cycloalkyl, aralkyl, aryl, CO₂ H, amino R² O, R² S(O)_(n).

Liebigs Ann. Chem. 1986, 1749-1764 teaches compounds of the formula:##STR12##

Where R^(X) is hydrogen, methyl, benzyloxy, or methoxy, and R³ iscarboethoxy.

These compounds differ from the compounds of the present invention.These compounds are not pyrrolopyrazines and also lack the various ringsubstituents of the compounds of the present invention.

SUMMARY OF THE INVENTION

This invention provides novel compounds of Formula I which interact witha GABAa binding site, the benzodiazepine receptor.

The invention provides pharmaceutical compositions comprising compoundsof Formula I. The invention also provides compounds useful in enhancingaltertness, treatment of seizure, anxiety, and sleep disorders, andtreatment of benzodiazepine overdoses. Accordingly, a broad embodimentof the invention is directed to compounds of Formula I: ##STR13## andthe pharmaceutically acceptable non-toxic salts thereof

wherein: ##STR14## represents: ##STR15## where n is 0, 1 or 2;

R₁ and R₂ are

the same or different and represent hydrogen or straight chain orbranched lower alkyl having 1-6 carbon atoms;

W is

phenyl, 2- or 3-thienyl, or 2-, 3-, or 4-pyridyl; or

phenyl, 2- or 3-thienyl, or 2-, 3-, or 4-pyridyl, each of which is monoor disubstituted with halogen, hydroxy, straight or branched chain loweralkyl having 1-6 carbon atoms, straight or branched chain lower alkoxyhaving 1-6 carbon atoms, amino, or mono- or dialkylamino where eachalkyl portion is straight or branched chain lower alkyl having 1-6carbon atoms; and

Y is

N--R₃ where R₃ is

hydrogen, straight or branched chain lower alkyl having 1-6 carbonatoms, phenyl, or phenylalkyl where the alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms; straight or branched chainlower alkoxy having 1-6 carbon atoms, or phenylalkoxy where the alkoxyis straight or branched chain lower alkoxy having 1-6 carbon atoms; or

--COR₄ or --SO₂ R₄ where R₄ is straight or branched chain lower alkylhaving 1-6 carbon atoms;

C═O, CR₆ OR₅, CR₆ COR₅, CR₆ CO₂ R₅, CR₆ OCOR₅, and CR₅ R₆, where

R₅ is hydrogen, straight or branched chain lower alkyl having 1-6 carbonatoms, phenyl, or phenylalkyl where the alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms; and

R₆ is hydrogen, or straight or branched chain lower alkyl having 1-6carbon atoms;

CR₆ CONR₇ R₈ or CR₆ (CH₂)_(n) NR₇ R₈ where n is 0, 1, or 2, and

R₆ and R₇ are the same or different and represent hydrogen, or straightor branched chain lower alkyl having 1-6 carbon atoms; and

R₈ is hydrogen, straight or branched chain lower alkyl having 1-6 carbonatoms, phenyl, pyridyl, or phenylalkyl where the alkyl is straight orbranched chain lower alkyl having 1-6 carbon atoms; or NR₇ R₈ ismorpholyl, piperidyl, pyrrolidyl, or N-alkyl piperazyl;

CR₆ NR₉ CO₂ R₁₀ where

R₆ is hydrogen, or straight or branched chain lower alkyl having 1-6carbon atoms, and

R₉ and R₁₀ are the same or different and represent hydrogen, straight orbranched chain lower alkyl having 1-6 carbon atoms, phenyl, orphenylalkyl where the alkyl is straight or branched chain lower alkylhaving 1-6 carbon atoms;

--CR₆ C(OH)R₁₁ R₁₂ where R₁₁ and R₁₂ are the same or different andrepresent straight or branched chain lower alkyl having 1-6 carbonatoms, phenyl, or phenylalkyl where the alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms, and R₆ is hydrogen, orstraight or branched chain lower alkyl having 1-6 carbon atoms; or

Y is

a group of the formula: ##STR16## where m is 0, 1, or 2, R₁₃ ishydrogen, straight or branched chain lower alkyl having 1-6 carbonatoms, phenyl, or phenylalkyl where the alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms;

Z is methylene, oxygen, NR₁₄ or CHCONR₁₄ where R₁₄ is hydrogen, straightor branched chain lower alkyl having 1-6 carbon atoms, phenyl, pyridyl,or phenylalkyl or pyridylalkyl where the alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms; and

T is methylene or oxygen;

A is CH or N;

B is N or CR₁₅ where

R₁₅ is

hydrogen, halogen, straight or branched chain lower alkyl having 1-6carbon atoms, phenyl, phenylalkyl where the alkyl is straight orbranched chain lower alkyl having 1-6 carbon atoms,

--COOR₁₆, --CONR₁₆ R₁₇, --COR₁₆ or --SO₂ R₁₆ where

R₁₆ is straight or branched chain lower alkyl having 1-6 carbon atoms,straight or branched chain lower alkoxy having 1-6 carbon atoms, orphenylalkyl where the alkyl is straight or branched chain lower alkoxyhaving 1-6 carbon atoms, and

R₁₇ is straight or branched chain lower alkyl having 1-6 carbon atoms;and

E is hydrogen, or straight or branched chain lower alkyl having 1-6carbon atoms.

These compounds are highly selective agonists, antagonists or inverseagonists for GABAa brain receptors or prodrugs thereof and are useful inthe diagnosis and treatment of anxiety, sleep, and seizure disorders,overdose with benzodiazepine drugs, and enhancement of memory.

BRIEF DESCRIPTION OF THE DRAWING

FIGS. 1A-1D show representative pyrrolopyrazines of the presentinvention.

DETAILED DESCRIPTION OF THE INVENTION

The novel compounds encompassed by the instant invention can bedescribed by the following general formula I: ##STR17## and thepharmaceutically acceptable non-toxic salts thereof

wherein: ##STR18## represents: ##STR19## where n is 0, 1 or 2;

R₁ and R₂ are

the same or different and represent hydrogen or straight chain orbranched lower alkyl having 1-6 carbon atoms;

W is

phenyl, 2- or 3-thienyl, or 2-, 3-, or 4-pyridyl; or phenyl, 2- or3-thienyl, or 2-, 3-, or 4-pyridyl, each of which is mono ordisubstituted with halogen, hydroxy, straight or branched chain loweralkyl having 1-6 carbon atoms, straight or branched chain lower alkoxyhaving 1-6 carbon atoms, amino, or mono- or dialkylamino where eachalkyl portion is straight or branched chain lower alkyl having 1-6carbon atoms; and

Y is

N--R₃ where R₃ is

hydrogen, straight or branched chain lower alkyl having 1-6 carbonatoms, phenyl, or phenylalkyl where the alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms; straight or branched chainlower alkoxy having 1-6 carbon atoms, or phenylalkoxy where the alkoxyis straight or branched chain lower alkoxy having 1-6 carbon atoms; or

--COR₄ or --SO₂ R₄ where R₄ is straight or branched chain lower alkylhaving 1-6 carbon atoms;

C═O, CR₆ OR₅, CR₆ COR₅, CR₆ CO₂ R₅, CR₆ OCOR₅, and CR₅ R₆, where

R₅ is hydrogen, straight or branched chain lower alkyl having 1-6 carbonatoms, phenyl, or phenylalkyl where the alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms; and

R₆ is hydrogen, or straight or branched chain lower alkyl having 1-6carbon atoms;

CR₆ CONR₇ R₈ or CR₆ (CH₂)_(n) NR₇ R₈ where n is 0, 1, or 2, and

R₆ and R₇ are the same or different and represent hydrogen, or straightor branched chain lower alkyl having 1-6 carbon atoms; and

R₈ is hydrogen, straight or branched chain lower alkyl having 1-6 carbonatoms, phenyl, pyridyl, or phenylalkyl where the alkyl is straight orbranched chain lower alkyl having 1-6 carbon atoms; or NR₇ R₈ ismorpholyl, piperidyl, pyrrolidyl, or N-alkyl piperazyl;

CR₆ NR₉ CO₂ R₁₀ where

R₆ is hydrogen, or straight or branched chain lower alkyl having 1-6carbon atoms, and

R₉ and R₁₀ are the same or different and represent hydrogen, straight orbranched chain lower alkyl having 1-6 carbon atoms, phenyl, orphenylalkyl where the alkyl is straight or branched chain lower alkylhaving 1-6 carbon atoms;

--CR₆ C(OH)R₁₁ R₁₂ where R₁₁ and R₁₂ are the same or different andrepresent straight or branched chain lower alkyl having 1-6 carbonatoms, phenyl, or phenylalkyl where the alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms, and R₆ is hydrogen, orstraight or branched chain lower alkyl having 1-6 carbon atoms; or

Y is

a group of the formula: ##STR20## where m is 0, 1, or 2, R₁₃ ishydrogen, straight or branched chain lower alkyl having 1-6 carbonatoms, phenyl, or phenylalkyl where the alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms;

Z is methylene, oxygen, NR₁₄ or CHCONR₁₄ where R₁₄ is hydrogen, straightor branched chain lower alkyl having 1-6 carbon atoms, phenyl, pyridyl,or phenylalkyl or pyridylalkyl where the alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms; and

T is methylene or oxygen;

A is CH or N;

B is N or CR₁₅ where

R₁₅ is

hydrogen, halogen, straight or branched chain lower alkyl having 1-6carbon atoms, phenyl, phenylalkyl where the alkyl is straight orbranched chain lower alkyl having 1-6 carbon atoms,

--COOR₁₆, --CONR₁₆ R₁₇, --COR₁₆ or --SO₂ R₁₆ where

R₁₆ is straight or branched chain lower alkyl having 1-6 carbon atoms,straight or branched chain lower alkoxy having 1-6 carbon atoms, orphenylalkyl where the alkyl is straight or branched chain lower alkoxyhaving 1-6 carbon atoms, and

R₁₇ is straight or branched chain lower alkyl having 1∝6 carbon atoms;and

E is hydrogen, or straight or branched chain lower alkyl having 1-6carbon atoms.

The present invention also encompasses compounds of general formula II:##STR21## wherein: n is 0, 1 or 2;

R₁ and R₂ are

the same or different and represent hydrogen or straight or branchedchain lower alkyl having 1-6 carbon atoms;

R₅ is

hydrogen, phenyl, straight or branched chain lower alkyl having 1-6carbon atoms, phenylalkyl where the alkyl is straight or branched chainlower alkyl having 1-6 carbon atoms; and

W is

phenyl, 2- or 3-thienyl, or 2-, 3-, or 4-pyridyl; or

phenyl, 2- or 3-thienyl, or 2-, 3-, or 4-pyridyl, each of which is monoor disubstituted with halogen, hydroxy, straight or branched chain loweralkyl having 1-6 carbon atoms, straight or branched chain lower alkoxyhaving 1-6 carbon atoms, amino, or mono- or dialkylamino where eachalkyl portion is straight or branched chain lower alkyl having 1-6carbon atoms.

The present invention also emcompasses compounds of general formula III:##STR22## where R₁ and R₂ are the same or different and representhydrogen or straight or branched chain lower alkyl having 1-6 carbonatoms;

W is

phenyl, 2- or 3-thienyl, or 2-, 3-, or 4-pyridyl; or

phenyl, 2- or 3-thienyl, or 2-, 3-, or 4-pyridyl, each of which is monoor disubstituted with halogen, hydroxy, straight or branched chain loweralkyl having 1-6 carbon atoms, straight or branched chain lower alkoxyhaving 1-6 carbon atoms, amino , or mono- or dialkylamino where eachalkyl portion is straight or branched chain lower alkyl having 1-6carbon atoms; and

R₃ is

hydrogen, straight or branched chain lower alkyl having 1-6 carbonatoms, phenyl, or phenylalkyl where the alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms; straight or branched chainlower alkoxy having 1-6 carbon atoms, or phenylalkoxy where the alkoxyis straight or branched chain lower alkoxy having 1-6 carbon atoms; or

--COR₄ or --SO₂ R₄ where R₄ is straight or branched chain lower alkylhaving 1-6 carbon atoms.

The present invention also emcompasses compounds of general formula IV:##STR23## where W is

phenyl, 2- or 3-thienyl, or 2-, 3-, or 4-pyridyl; or

phenyl, 2- or 3-thienyl, or 2-, 3-, or 4-pyridyl, each of which is monoor disubstituted with halogen, hydroxy, straight or branched chain loweralkyl having 1-6 carbon atoms, straight or branched chain lower alkoxyhaving 1-6 carbon atoms, amino, or mono- or dialkylamino where eachalkyl portion is straight or branched chain lower alkyl having 1-6carbon atoms; and

Z is

methylene, oxygen, NR₁₄ or CHCONR₁₄ where R₁₄ is hydrogen, straight orbranched chain lower alkyl having 1-6 carbon atoms, phenyl, pyridyl, orphenylalkyl or pyridylalkyl where the alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms; and

T is methylene or oxygen; and

U is methylene or carbonyl.

The present invention also emcompasses compounds of general formula V:##STR24## where W is

phenyl, 2- or 3-thienyl, or 2-, 3-, or 4-pyridyl; or

phenyl, 2- or 3-thienyl, or 2-, 3-, or 4-pyridyl, each of which is monoor disubstituted with halogen, hydroxy, straight or branched chain loweralkyl having 1-6 carbon atoms, straight or branched chain lower alkoxyhaving 1-6 carbon atoms, amino, or mono- or dialkylamino where eachalkyl portion is straight or branched chain lower alkyl having 1-6carbon atoms; and

E is

hydrogen, or straight or branched chain lower alkyl having 1-6 carbonatoms, and

R₁₅ is

hydrogen, halogen, straight or branched chain lower alkyl having 1-6carbon atoms, phenyl, phenylalkyl where the alkyl is straight orbranched chain lower alkyl having 1-6 carbon atoms, --COOR₁₆, --CONR₁₆R₁₇, --COR₁₆ or --SO₂ R₁₆ where

R₁₆ is straight or branched chain lower alkyl having 1-6 carbon atoms,straight or branched chain lower alkoxy having 1-6 carbon atoms, orphenylalkyl where the alkyl is straight or branched chain lower alkoxyhaving 1-6 carbon atoms and

R₁₇ is straight or branched chain lower alkyl having 1-6 carbon atoms.

Non-toxic pharmaceutical salts include salts of acids such ashydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic,toluene sulfonic, hydroiodic, acetic and the like. Those skilled in theart will recognize a wide variety of non-toxic pharmaceuticallyacceptable addition salts.

By lower alkyl in the present invention is meant straight or branchedchain alkyl groups having 1-6 carbon atoms, such as, for example,methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl,pentyl, 2pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and3-methylpentyl.

By lower alkoxy in the present invention is meant straight or branchedchain alkoxy groups having 1-6 carbon atoms, such as, for example,methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy,pentoxy, 2-pentoxy, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy,and 3-methylpentoxy.

By halogen in the present invention is meant fluorine, bromine, chlorineand iodine.

By N-alkyl piperazyl in the invention is meant radicals of the formula:##STR25## where R is a straight or branched chain lower alkyl as definedabove.

Representative compounds of the present invention, which are encompassedby Formula I, include, but are not limited to the compounds in FIGS.1A-1D and their pharmaceutically acceptable salts.

The pharmaceutical utility of compounds of this invention are indicatedby the following assay for GABAa receptor activity.

Assays are carried out as described in Thomas and Tallman (J. Bio. Chem.156: 9838-9842, J. Neurosci. 3:433-440, 1983). Rat cortical tissue isdissected and homogenized in 25 volumes (w/v) of 0.05M Tris HCl buffer(pH 7.4 at 4° C.). The tissue homogenate is centrifuged in the cold (4°)at 20,000×g for 20'. The supernatant is decanted and the pellet isrehomogenized in the same volume of buffer and again centrifuged at20,000×g. The supernatant is decanted and the pellet is frozen at -20°C. overnight. The pellet is then thawed and rehomogenized in 25 volume(original wt/vol) of buffer and the procedure is carried out twice. Thepellet is finally resuspended in 50 volumes (w/vol of 0.05M Tris HClbuffer (pH 7.4 at 40° C.).

Incubations contain 100 μl of tissue homogenate, 100 μl of radioligand0.5 nM (³ H-RO15-1788 [³ H-Flumazenil] specific activity 80 Ci/mmol),drug or blocker and buffer to a total volume of 500 μl. Incubations arecarried for 30 min at 4° C. then are rapidly filtered through GFBfilters to separate free and bound ligand. Filters are washed twice withfresh 0.05M Tris HCl buffer (pH 7.4 at 4° C.) and counted in a liquidscintillation counter. 1.0 μM diazepam is added to some tubes todetermine nonspecific binding. Data are collected in triplicatedeterminations, averaged and % inhibition of total specific binding iscalculated. Total Specific Binding=Total-Nonspecific. In some cases, theamounts of unlabeled drugs is varied and total displacement curves ofbinding are carried out. Data are converted to a form for thecalculation of IC₅₀ and Hill Coefficient (nH).

Data for the compounds of this invention are listed in Table I.

                  TABLE I                                                         ______________________________________                                        Compound Number.sup.1                                                                          IC.sub.50 (μM)                                            ______________________________________                                         1               0.200                                                         5               0.045                                                        11               0.029                                                        12               0.533                                                        ______________________________________                                    

Compounds 1, 5 and 11 are particularly preferred embodiments of thepresent invention because of their potency in binding to the GABAareceptor.

The compounds of general formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques. In addition, there isprovided a pharmaceutical formulation comprising a compound of generalformula I and a pharmaceutically acceptable carrier. One or morecompounds of general formula I may be present in association with one ormore non-toxic pharmaceutically acceptable carriers and/or diluentsand/or adjuvants and if desired other active ingredients. Thepharmaceutical compositions containing compounds of general formula Imay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsion, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with nontoxic pharmaceutically acceptableexcipients which are suitable for the manufacture of tablets. Theseexcipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monoleate, and condensation products ofthe said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monoleate. The emulsions may also contain sweetening andflavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitol or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be sterile injectablesolution or suspension in a non-toxic parenterally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of general formula I may also be administered in the formof suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenonirritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

Compounds of general formula I may be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anaesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment of theaboveindicated conditions (about 0.5 mg to about 7 g per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of an active ingredient.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

An illustration of the preparation of compounds of the present inventionis given in Scheme I. Those having skill in the art will recognize thatthe starting materials may be varied and additional steps employed toproduce compounds encompassed by the present invention, as demonstratedby the following examples. ##STR26## where n is 0, 1 or 2;

R₁ and R₂ are the same or different and represent hydrogen or straightchain or branched lower alkyl having 1-6 carbon atoms;

W is

phenyl, 2- or 3-thienyl, or 2-, 3-, or 4-pyridyl; or

phenyl, 2- or 3-thienyl, or 2-, 3-, or 4-pyridyl, each of which is monoor disubstituted with halogen, hydroxy, straight or branched chain loweralkyl having 1-6 carbon atoms, straight or branched chain lower alkoxyhaving 1-6 carbon atoms, amino, or mono- or dialkylamino where eachalkyl portion is straight or branched chain lower alkyl having 1-6carbon atoms; and

Y is

N--R₃ where R₃ is

hydrogen, straight or branched chain lower alkyl having 1-6 carbonatoms, phenyl, or phenylalkyl where the alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms; straight or branched chainlower alkoxy having 1-6 carbon atoms, or phenylalkoxy where the alkoxyis straight or branched chain lower alkoxy having 1-6 carbon atoms; or

--COR₄ or --SO₂ R₄ where R₄ is straight or branched chain lower alkylhaving 1-6 carbon atoms;

C═O, CR₆ OR₅, CR₆ COR₅, CR₆ CO₂ R₅, CR₆ OCOR₅, and CR₅ R₆, where

R₅ is hydrogen, straight or branched chain lower alkyl having 1-6 carbonatoms, phenyl, or phenylalkyl where the alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms; and

R₆ is hydrogen, or straight or branched chain lower alkyl having 1-6carbon atoms;

CR₆ CONR₇ R₈ or CR₆ (CH₂)_(n) NR₇ R₈ where n is 0, 1, or 2, and

R₆ and R₇ are the same or different and represent hydrogen, or straightor branched chain lower alkyl having 1-6 carbon atoms; and

R₈ is hydrogen, straight or branched chain lower alkyl having 1-6 carbonatoms, phenyl, pyridyl, or phenylalkyl where the alkyl is straight orbranched chain lower alkyl having 1-6 carbon atoms; or

NR₇ R₈ is morpholyl, piperidyl, pyrrolidyl, or N-alkyl piperazyl;

CR₆ NR₉ CO₂ R₁₀ where

R₆ is hydrogen, or straight or branched chain lower alkyl having 1-6carbon atoms, and

R₉ and R₁₀ are the same or different and represent hydrogen, straight orbranched chain lower alkyl having 1-6 carbon atoms, phenyl, orphenylalkyl where the alkyl is straight or branched chain lower alkylhaving 1-6 carbon atoms;

--CR₆ C(OH)R₁₁ R₁₂ where R₁₁ and R₁₂ are the same or different andrepresent straight or branched chain lower alkyl having 1-6 carbonatoms, phenyl, or phenylalkyl where the alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms, and R₆ is hydrogen, orstraight or branched chain lower alkyl having 1-6 carbon atoms; or

Y is

a group of the formula: ##STR27## where m is 0, 1, or 2, R₁₃ ishydrogen, straight or branched chain lower alkyl having 1-6 carbonatoms, phenyl, or phenylalkyl where the alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms;

Z is methylene, oxygen, NR₁₄ or CHCONR₁₄ where R₁₄ is hydrogen, straightor branched chain lower alkyl having 1-6 carbon atoms, phenyl, pyridyl,or phenylalkyl or pyridylalkyl where the alkyl is straight or branchedchain lower alkyl having 1-6 carbon atoms; and

T is methylene or oxygen;

B is N or CR₁₅ where

R₁₅ is

hydrogen, halogen, straight or branched chain lower alkyl having 1-6carbon atoms, phenyl, phenylalkyl where the alkyl is straight orbranched chain lower alkyl having 1-6 carbon atoms,

--COOR₁₆, --CONR₁₆ R₁₇, --COR₁₆ or --SO₂ R₁₆ where

R₁₆ is straight or branched chain lower alkyl having 1-6 carbon atoms,straight or branched chain lower alkoxy having 1-6 carbon atoms, orphenylalkyl where the alkyl is straight or branched chain lower alkoxyhaving 1-6 carbon atoms and

R₁₇ is straight or branched chain lower alkyl having 1-6 carbon atoms;and

E is hydrogen, or straight or branched chain lower alkyl having 1-6carbon atoms.

The invention is illustrated further by the following examples which arenot to be construed as limiting the invention in scope or spirit to thespecific procedures and compounds described in them.

EXAMPLE I ##STR28##

An aqueous solution of glycinamide (0.027 mol, 3.03 g), which wasprepared by neutralizing glycinamide hydrochloride with one equivalentof 10N NaOH, was slowly added to a stirring solution of2-fluoro-5-methoxyphenyl glyoxal (0.027 mol, 5.42 g) in MeOH (35 mL) at0° C. One equivalent of 10N NaOH (2.74 mL) was then added slowly to theresulting clear orange solution. After stirring overnight at roomtemperature the solution was acidified to pH˜3 with 12N HCl and themethanol was evaporated under reduced pressure. The residue waspartitioned between CH₂ Cl₂ and water and the aqueous phase wasextracted (5×) with CH₂ Cl₂. The combined CH₂ Cl₂ portions were dried(Na₂ SO₄) and concentrated under reduced pressure to give a dark solid.The solid was dissolved in CH₂ Cl₂ /MeOH, heated for five minutes withdecolorizing charcoal and filtered through 2 inches of silica gel (5%MeOH/CH₂ Cl₂ eluent). Evaporation of the solvents under reduced pressureafforded 5-(2-fluoro-5-methoxyphenyl)-pyrazin-2-one.

EXAMPLE II ##STR29##

A solution of 5-(2-fluoro-5-methoxyphenyl)-pyrazin-2-one in POCl₃ washeated at 100° C.-110° C. in a sealed tube for 16 h. After evaporatingthe remaining POCl₃ under reduced pressure, the brown residue was takenup in EtOAc and washed (3×) with saturated aqueous NaHCO₃ solution. TheEtOAc solution was then dried (Na₂ SO₄) and concentrated under reducedpressure leaving a brown oil. The oil was filtered through a pad ofsilica gel (30% EtOAc/hexanes eluent) and the solvents were againevaporated under reduced pressure. The oil was taken up in CH₂ Cl₂,heated for 5 min. with decolorizing charcoal and filtered throughcelite. Evaporation of the solvent afforded2-chloro-5-(2-fluoro-5-methoxyphenyl) pyrazine as a light-brown oil.

EXAMPLE III ##STR30##

An ethanolic solution of 2-chloro-5-(2-fluoro-5-methoxyphenyl) pyrazineand hydrazine monohydrate (10 equiv.) was refluxed under a N₂ atmospherefor 6 h. The ethanol was removed under reduced pressure and the residuewas partitioned between 5% HCl and CH₂ Cl₂. The CH₂ Cl₂ layer wasextracted several times with 5% HCl and the combined aqueous portionswere washed (1×) with CH₂ Cl₂. The aqueous solution was made basic with10N NaOH and then extracted (4×) with CH₂ Cl₂. The combined CH₂ Cl₂portions were washed (1×) with brine, dried (Na₂ SO₄), treated withdecolorizing charcoal and filtered through celite. Evaporation of thesolvent under reduced pressure yielded2-hydrazino-5-(2-fluoro-5-methoxyphenyl)-pyrazine as a beige oil.

EXAMPLE IV ##STR31##

A solution of 2-hydrazino-5-(2-fluoro-5-methoxyphenyl)-pyrazine (461 mg,1.97 mmol) and cyclohexane (1.1 eq., 0.224 mL, 2.16 mmol) in anhydrousethanol (20 mL) was refluxed for 1-1.5 h whereupon the hydrazine was nolonger visible on TLC (5% MeOH/CH₂ Cl₂ eluent). The reaction mixture wasconcentrated under reduced pressure and the residue triturated withether/hexanes. The resulting solid was washed thoroughly with hexanesand dried under vacuum to afford the hydrazone in near quantitativeyield.

EXAMPLE V ##STR32##

A solution of the hydrazone in diethylene glycol was refluxed for 1 hand then poured into ice water. The cloudy solution was extracted (4×)with EtOAc and the combined organic portions were washed (1×) withbrine. The EtOAc solution was dried (Na₂ SO₄), treated with decolorizingcharcoal, filtered through celite and then concentrated under reducedpressure. Flash chromatography of the residue (30% EtOAc/hexanes to 40%EtOAc/hexanes eluent) afforded a light-yellow oil which upon triturationwith hexanes/EtOAc yielded a light-yellow solid. The solid was rinsedwith hexanes and dried under vacuum to give pure2-(2-Fluoro-5-methoxyphenyl)-6,7,8,9-tetrahydro-5H-indolo[2,3-b]pyrazine(Compound 1).

EXAMPLE VI ##STR33##

A sealed tube containing2-(2-Fluoro-5-methoxyphenyl)-6,7,8,9-tetrahydro-indolo[2,3-b]pyrazine(46 mg, 0.155 mmol), cyclohexane (10 equiv., 0.157 mL, 1.55 mmol), Pdblack (35 mg) and mesitylene (10 mL) was heated to 200° C. in an oilbath and the contents stirred via a magnetic stir bar. The progress ofthe reaction was monitored by intermittently opening the cooled tube andtaking out an aliquot for TLC analysis (30% ethyl acetate/hexaneseluent; the aromatized product has a slightly larger R_(f) value thanthat of the starting material). Upon completion of the reaction, themixture was filtered through celite and the mesitylene removed using ahigh vacuum rotary evaporator. Recrystallization from hexanes/ethylacetate afforded 2-(2-Fluoro-5-methoxyphenyl)-5H-indolo[2,3-b]pyrazine(Compound 2) as an off-white solid.

EXAMPLE VII ##STR34##

To a mixture of 4-bromo-1-butene (1.0 g) and magnesium turnings (1.77 g)in dry tetrahydrofuran (10 mL) was added a crystal of iodine and themixtures was stirred at room temperature until complete reaction hadoccurred. To this mixture was added 1,4-cyclohexanedione monoethyleneketal (780 mg) in tetrahydrofuran (1 mL) at 0° C. After 1 h at 0° C. and1 h at room temperature the reaction mixture was diluted with ammoniumchloride solution and the product was extracted with ether. After dryingover magnesium sulfate the solvent was removed in vacuo and the residuewas subjected to flash chromatography with 25% ethyl acetate /hexane asthe eluent to afford 4-(3-Butenyl)-4-hydroxy-cyclohexanone ethyleneketal as an oil.

EXAMPLE VIII ##STR35##

A mixture of 4-(3-Butenyl)-4-hydroxy-cyclohexanone ethylene ketal (1.8g) in methanol (40 mL) was ozonized at -70° C. until a persistant bluecolor was obtained. The ozonide was decomposed with excess sodiumborohydride at -60° C. The reaction was concentrated in vacuo and theresidue was partitioned between brine and ethyl acetate. The aqueouslayer was extracted several more times with ethyl acetate and thecombined organic extracts were dried over magnesium sulfate and thesolvent was removed in vacuo. The residue was purified by flashchromatography with ethyl acetate as the eluent to afford4-(3-Hydroxypropyl)-4-hydroxy-cyclohexanone ethylene ketal as an oil.

EXAMPLE IX ##STR36##

Air was bubbled into a solution of cuprous chloride (30 mg) andpalladium dichloride (5 mg) in dimethylformamide (7.5 mL) and water (3mL) for 2 h. 4-(3-Butenyl)-4-hydroxy-cyclohexanone ethylene ketal (300mg) was added and the reaction was continued for 36 h. The reactionmixture was diluted with water and the product was extracted withmethylene chloride. After drying over magnesium sulfate the solvent wasremoved in vacuo. The residue was dissolved in ethanol and treated withexcess sodium borohydride. After 2 h at room temperature the reactionwas worked up as before and the residue was subjected to flashchromatography with ethyl acetate as the eluent to afford4-(3-Hydroxybutyl)-4-hydroxy-cyclohexanone ethylene ketal as an oil.

EXAMPLE X ##STR37##

A mixture of 4-(3-Hydroxypropyl)-4-hydroxy-cyclohexanone ethylene ketal(1.4 g) and diisopropylethylamine (3.37 mL) in methylene chloride (100mL) at -78° C. was treated with triflic anhydride (1.64 mL). After 30min the reaction mixture was washed with water, the solvent was driedover magnesium sulfate and removed in vacuo. The residue was dissolvedin 30 mL of tetrahydrofuran and 15 mL of 3% HCl. After 5 h at roomtemperature the reaction mixture was diluted with water and the productwas extracted with ether. After drying over magnesium sulfate thesolvent was removed in vacuo to afford 1-Oxaspiro[4.5]decan-8-one as anoil.

EXAMPLE XI ##STR38##

A mixture of Cyclohexane-1,4-dione monoethylene ketal (2.0 g),N-Methyl-hydroxylamine hydrochloride (1.079 g), sodium bicarbonate (1.09g) and ethanol (20 mL) was stirred at room temperature for 18 h. Theethanol was removed in vacuo and the residue was taken up in 30 mL oftoluene. After filtration, ethyl acrylate (2.2 g) was added to thefiltrate and the resulting mixture was heated for 4 h at 100° C. Thesolvent was removed in vacuo and the resulting isoxazolo derivative waspurified by flash chromatography on silica gel with 50% ethylacetate/hexane as the eluent. This material was hydrogenated at 45 psiin 50 mL of acetic acid over 10% palladium on carbon catalyst (400 mg)at room temperature for 16 h. After filtration and removal of solventthe residue was purified by filtration through silica gel with ethylacetate as the eluent to afford3-Hydroxy-1-methyl-1-azaspiro[4.5]decane-2,8-dione ethylene ketal as anoil.

EXAMPLE XII ##STR39##

To a mixture of 3-Hydroxy-1-methyl-1-azaspiro[4.5]decane-2,8-dioneethylene ketal (1.0 g), triethylamine (1.73 mL) and methylene chloride(10 mL) was added methanesulfonyl chloride (950 mg) dissolved inmethylene chloride (5 mL) in a dropwise fashion at 0° C. After 30 minthe reaction mixture was washed with water, the organic layer dried overmagnesium sulfate and the solvent was removed in vacuo. The resultingresidue was filtered through silica gel with ethyl acetate as the eluentto afford 3-Mesyloxy-1-methyl-1-azaspiro[4.5]decane-2,8-dione ethyleneketal as an oil.

EXAMPLE XIII ##STR40##

A mixture of 3-Mesyloxy-1-methyl-1-azaspiro[4.5]decane-2,8-dioneethylene ketal (1.28 g), sodium iodide (1.8 g) and acetone (20 mL) wasrefluxed with stirring for 90 min. The solvent was removed in vacuo andthe residue was dissolved in methylene chloride and washed with water.After drying over magnesium sulfate the solvent was removed in vacuo.The residue was dissolved in toluene (20 mL) and treated withtri-n-butyltin hydride (1.75 g) and AIBN (20 mg) and the resultingmixture was heated at 110° C. for 1 h. After removal of the solvent theresidue was chromatographed on silica gel with ethyl acetate as theeluent. The resulting product was stirred with a mixture of water (5mL), 3N HCl (1.5 mL) and acetic acid (2 mL) for 16 h. The resultingproduct was extracted 3 times with methylene chloride, washed withsodium bicarbonate solution, dried over magnesium sulfate and thesolvent was removed in vacuo to afford 1-Methyl-1-azaspiro[4.5]decane-2,8-dione as an oil.

EXAMPLE XIV

The following compounds were prepared according to the proceduredescribed in Examples I-XIII:

a) 2-Phenyl-6,7,8,9-tetrahydro-5H-indolo[2,3-b]pyrazine (Compound 3),m.p. 234°-236° C.

b) 2-Phenyl-5H-indolo[2,3-b]pyrazine (Compound 4).

c) 2-(2-Fluorophenyl)-6,7,8,9-tetrahydro-5H-indolo[2,3-b]pyrazine(Compound 5), m.p. 212°-214° C.

d) 2-(2-Fluorophenyl)-5H-indolo[2,3-b]pyrazine (Compound 6).

e) 2-(4-Methoxyphenyl)-6,7,8,9-tetrahydro-5H-indolo[2,3-b]pyrazine(Compound 7), m.p. 129°-132° C.

f) 2-(4-Methoxyphenyl)-5H-indolo[2,3-b]pyrazine (Compound 8).

g) 2-(3-Methoxyphenyl)-6,7,8,9-tetrahydro-5H-indolo[2,3-b]pyrazine(Compound 9).

h) 2-(3-Methoxyphenyl)-5H-indolo[2,3-b]pyrazine (Compound 10).

i)2-(2-Fluoro-4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-indolo[2,3-b]pyrazine(Compound 11).

j) 2-(2-Fluoro-4-methoxyphenyl)-5H-indolo[2,3-b]pyrazine (Compound 12),m.p. 216°-218° C.

k) 2-(3-Ethoxyphenyl)-6,7,8,9-tetrahydro-5H-indolo[2,3-b]pyrazine(Compound 13).

l) 2-(3-Ethoxyphenyl)-5H-indolo[2,3-b]pyrazine (Compound 14).

m)2'-Phenyl-4,5,5',6',7',9'-hexahydro-spiro[furan-2,8'(3H)indolo[2,3-b]-pyrazine](Compound 15).

n)2'-(4-Methoxyphenyl)-5',6',7',9'-tetrahydro-spiro[(1,3)dioxolane-2,8'-indolo[2,3-b]-pyrazine](Compound 16).

o)2'-(4-Methoxyphenyl)-4,5,5',6',7',9'-hexahydro-spiro[furan-2,8'(3H)-indolo[2,3-b]-pyrazine](Compound 17).

p)2'-(2-Fluorophenyl)-4,5,5',6',7',9'-hexahydro-spiro[furan-2,8'(3H)-indolo[2,3-b]-pyrazine](Compound 18).

q)2'-(2-Fluorophenyl)-5',6',7',9'-tetrahydro-spiro[(1,3)dioxolane-2,8'-indolo[2,3-b]-pyrazine](Compound 19).

r)1'-Methyl-2-(2-fluorophenyl)-5,6,7,9-tetrahydro-spiro[indolo[2,3-b]-pyrazine-2',8-pyrrolidin-5'-one](Compound 20).1'-Methyl-2-(4-methoxyphenyl)-5,6,7,9-tetrahydro-spiro[indolo[2,3-b]-pyrazine-2',8-pyrrolidin-5'-one](Compound 21).

t) 2-(2-Thienyl)-6,7,8,9-tetrahydro-5H-indolo[2,3-b]pyrazine (Compound22).

u) 2-(2-Thienyl)-5H-indolo[2,3-b]pyrazine (Compound 23).

The invention and the manner and process of making and using it, are nowdescribed in such full, clear, concise and exact terms as to enable anyperson skilled in the art to which it pertains, to make and use thesame. It is to be understood that the foregoing describes preferredembodiments of the present invention and that modifications may be madetherein without departing from the spirit or scope of the presentinvention as set forth in the claims. To particularly point out anddistinctly claim the subject matter regarded as invention, the followingclaims conclude this specification.

What is claimed is:
 1. A compound of the formula: ##STR41## or thepharmaceutically acceptable non-toxic salts thereof wherein: ##STR42##represents: ##STR43## where n is 0, 1 or 2; R₁ and R₂ arethe same ordifferent and represent hydrogen or straight chain or branched loweralkyl having 1-6 carbon atoms; W isphenyl, 2- or 3-thienyl, or 2-, 3-,or 4-pyridyl; or phenyl, 2- or 3-thienyl, or 2-, 3-, or 4-pyridyl, eachof which is mono or disubstituted with halogen, hydroxy, straight orbranched chain lower alkyl having 1-6 carbon atoms, straight or branchedchain lower alkoxy having 1-6 carbon atoms, amino, or mono- ordialkylamino where each alkyl portion is straight or branched chainlower alkyl having 1-6 carbon atoms; and Y isC═O, CR₆ OR₅, CR₆ COR₅, CR₆CO₂ R₅, CR₆ OCOR₅, and CR₅ R₆, whereR₅ is hydrogen, straight or branchedchain lower alkyl having 1-6 carbon atoms, phenyl, or phenylalkyl wherethe alkyl is straight or branched chain lower alkyl having 1-6 carbonatoms; and R₆ is hydrogen, or straight or branched chain lower alkylhaving 1-6 carbon atoms; CR₆ CONR₇ R₈ or CR₆ (CH₂)_(n) NR₇ R₈ where n is0, 1, or 2, andR₆ and R₇ are the same or different and representhydrogen, or straight or branched chain lower alkyl having 1-6 carbonatoms; and R₈ is hydrogen, straight or branched chain lower alkyl having1-6 carbon atoms, phenyl, pyridyl, or phenylalkyl where the alkyl isstraight or branched chain lower alkyl having 1-6 carbon atoms; or NR₇R₈ is morpholyl, piperidyl, pyrrolidyl, or N-alkyl piperazyl; CR₆ NR₉CO₂ R₁₀ whereR₆ is hydrogen, or straight or branched chain lower alkylhaving 1-6 carbon atoms, and R₉ and R₁₀ are the same or different andrepresent hydrogen, straight or branched chain lower alkyl having 1-6carbon atoms, phenyl, or phenylalkyl where the alkyl is straight orbranched chain lower alkyl having 1-6 carbon atoms; -CR₆ C(OH)R₁₁ R₁₂where R₁₁ and R₁₂ are the same or different and represent straight orbranched chain lower alkyl having 1-6 carbon atoms, phenyl, orphenylalkyl where the alkyl is straight or branched chain lower alkylhaving 1-6 carbon atoms, and R₆ is hydrogen, or straight or branchedchain lower alkyl having 1-6 carbon atoms; or Y isa group of theformula: ##STR44## where m is 0, 1, or 2, R₁₃ is hydrogen, straight orbranched chain lower alkyl having 1-6 carbon atoms, phenyl, orphenylalkyl where the alkyl is straight or branched chain lower alkylhaving 1-6 carbon atoms;Z is methylene, oxygen, NR₁₄ or CHCONR₁₄ whereR₁₄ is hydrogen, straight or branched chain lower alkyl having 1-6carbon atoms, phenyl, pyridyl, or phenylalkyl or pyridylalkyl where thealkyl is straight or branched chain lower alkyl having 1-6 carbon atoms;and T is methylene or oxygen.
 2. A compound of the formula: ##STR45##wherein: n is 0, 1 or 2;R₁ and R₂ arethe same or different and representhydrogen or straight or branched chain lower alkyl having 1-6 carbonatoms; R₅ ishydrogen, phenyl, straight or branched chain lower alkylhaving 1-6 carbon atoms, phenylalkyl where the alkyl is straight orbranched chain lower alkyl having 1-6 carbon atoms; and W isphenyl, 2-or 3-thienyl, or 2-, 3-, or 4-pyridyl; or phenyl, 2- or 3-thienyl, or2-, 3-, or 4-pyridyl, each of which is mono or disubstituted withhalogen, hydroxy, straight or branched chain lower alkyl having 1-6carbon atoms, straight or branched chain lower alkoxy having 1-6 carbonatoms, amino, or mono- or dialkylamino where each alkyl portion isstraight or branched chain lower alkyl having 1-6 carbon atoms.
 3. Acompound of the formula: ##STR46## where W isphenyl, 2- or 3-thienyl, or2-, 3-, or 4-pyridyl; or phenyl, 2- or 3-thienyl, or 2-, 3-, or4-pyridyl, each of which is mono or disubstituted with halogen, hydroxy,straight or branched chain lower alkyl having 1-6 carbon atoms, straightor branched chain lower alkoxy having 1-6 carbon atoms, amino, or mono-or dialkylamino where each alkyl portion is straight or branched chainlower alkyl having 1-6 carbon atoms; and Z ismethylene, oxygen, NR₁₄ orCHCONR₁₄ where R₁₄ is hydrogen, straight or branched chain lower alkylhaving 1-6 carbon atoms, phenyl, pyridyl, or phenylalkyl or pyridylalkylwhere the alkyl is straight or branched chain lower alkyl having 1-6carbon atoms; and T is methylene or oxygen; and U is methylene orcarbonyl.
 4. A compound according to claim 1, where W is2-fluoro-5-methoxyphenyl.
 5. A compound according to claim 3, where W is2-fluorophenyl.
 6. A compound according to claim 1, where W is2-fluoro-4-methoxyphenyl.
 7. A compound according to claim 1 which is2-(2-Fluoro-5-methoxyphenyl)-6,7,8,9-tetrahydro-5H-indolo[2,3-b]pyrazine.8. A compound according to claim 1 which is2-Phenyl-6,7,8,9-tetrahydro-5H-indolo[2,3-b]pyrazine.
 9. A compoundaccording to claim 1 which is2-(2-Fluorophenyl)-6,7,8,9-tetrahydro-5H-indolo[2,3-b]pyrazine.
 10. Acompound according to claim 1 which is2-(4-Methoxyphenyl)-6,7,8,9-tetrahydro-5H-indolo[2,3-b]pyrazine.
 11. Acompound according to claim 1 which is2-(3-Methoxyphenyl)-6,7,8,9-tetrahydro-5H-indolo[2,3-b]pyrazine.
 12. Acompound according to claim 1 which is2-(2-Fluoro-4-methoxyphenyl)-6,7,8,9-tetrahydro-5H-indolo[2,3-b]pyrazine.13. A compound according to claim 1 which is2-(3-Ethoxyphenyl)-6,7,8,9-tetrahydro-5H-indolo[2,3-b]pyrazine.
 14. Acompound according to claim 1 which is2'-Phenyl-4,5,5',6',7',9'-hexahydro-spiro[furan-2,8'(3H)-indolo[2,3-b]-pyrazine].15. A compound according to claim 1 which is2'-(4-Methoxyphenyl)-5',6',7',9'-tetrahydro-spiro[(1,3)dioxolane-2,8'-indolo[2,3-b]-pyrazine].16. A compound according to claim 1 which is2'-(4-Methoxyphenyl)-4,5,5',6',7',9'-hexahydro-spiro[furan-2,8'(3H)-indolo[2,3-b]-pyrazine].17. A compound according to claim 1 which is2'-(2-Fluorophenyl)-4,5,5',6',7',9'-hexahydro-spiro[furan-2,8'(3H)-indolo[2,3-b]-pyrazine].18. A compound according to claim 1 which is2'-(2-Fluorophenyl)-5',6',7',9'-tetrahydro-spiro[(1,3)dioxolane-2,8'-indolo[2,3-b]-pyrazine].19. A compound according to claim 1 which is1'-Methyl-2-(2-fluorophenyl)-5,6,7,9-tetrahydro-spiro[indolo[2,3-b]-pyrazine-2',8-pyrrolidin-5'-one].20. A compound according to claim 1 which is1'-Methyl-2-(4-methoxyphenyl)-5,6,7,9-tetrahydro-spiro[indolo[2,3-b]-pyrazine-2',8-pyrrolidin-5'-one].21. A compound according to claim 1 which is2-(2-Thienyl)-6,7,8,9-tetrahydro-5H-indolo[2,3-b]pyrazine.